Large-scale clinical studies in thalassemia have been limited by the small numbers of patients followed at any Center in North America. The establishment of a Clinical Research Network, as proposed in the current RFA, opens the way to important new studies for better diagnosis and management of thalassemia, and the prevention of long-term complications of the disease. Cardiac disease remains the major cause of early death among patients with transfusion-dependent beta-thalassemia major, and is often related to poor compliance with prescribed chelation regimens. Hepatitis C virus infections are also common in patients born before universal screening of the blood supply, and are a significant cause of morbidity. The two studies in this Proposal will address important aspects of these diseases. It has been observed that patients who present with significant cardiac disease, chiefly left ventricular dysfunction, improve rapidly after being started on an intensive chelation program. The rate of improvement is often too rapid to be accounted for by clearance of substantial amounts of iron from the body. This observation has led to the hypothesis that the cardiac toxicity of iron is not due to tissue deposition per se, but to a local depressant effect. This hypothesis has found experimental support in studies of non transferrin-bound plasma iron (NTBPI), which is highly toxic to cardiac and liver cells. Levels of NTBPI are are frequently elevated in inadequately chelated patients, and normalize rapidly after institution of adequate chelation regimens. We propose to evaluate the effectiveness of aggressive chelation therapy in reversing myocardial dysfunction, as determined clinically and by specialized echocardiographic measures, and correlating the improvement in function with changes in NTBPI and hepatic iron concentration (which is the most accurate correlate of total body iron burden). These studies will provide direct insight into mechanisms of myocardial dysfunction in patients with thalassemia, and will also allow us to prospectively evaluate the efficacy of aggressive chelation regimens. The second protocol is designed to assess the efficacy of a new drug regimen in treatment of chronic Hepatitis C virus infections. The most effective drug regimen for treatment of Hepatitis C (interferon-alpha + ribavirin) is quite toxic in thalassemia patients, as ribavirin causes significant red cell breakdown. A chemically-modified form of interferon (PEG-IFN), which persists in the circulation for much longer than conventional interferon, has recently been developed. Preliminary clinical studies suggest that therapy with PEG-IFN alone is as effective as current combination therapy, and has fewer toxicities. We therefore propose to evaluate the response of Hepatitis C-infected thalassemia patients to treatment with PEG-IFN alone, lend to treat patients who do not respond to PEG- IFN monotherapy with this drug in combination with ribavirin. Endpoints of this study will include end-of-treatment and sustained viral elimination, and changes in measures of hepatic inflammation. This study, when carried out in the context of a clinical trials network, will allow us to evaluate a promising new therapy more rapidly and with greater statistical power than would otherwise be possible.